Cholera, an illness caused by the bacterium Vibrio cholerae, causes 21,000 to 143,000 deaths per year. This diarrheal disease is very painful and can be fatal for those who become infected. Antibiotic treatments, like doxycycline, are vital in accelerating treatment and making it less costly. This is important especially since cholera is prevalent in countries with poor access to healthcare and sanitation. Cholera is now endemic in fifty countries, including Haiti. Without treatment, death can occur within hours. Study on this disease and its treatment would be vital in saving hundreds of thousands of lives worldwide. This disease could be easily prevented if low-cost treatment and sanitary water were more accessible, but instead, thousands of people die from cholera every year.
During the 1800s, cholera spread across the world from its origin in the Ganges delta in India. There were six subsequent pandemics that killed millions of people across all continents. The current pandemic started in South Asia in 1961, and reached Africa in 1971 and the Americas in 1991. It affects 1.3 to 4.0 million people per year. There are many strains of V. cholerae, but only two (O1 and O139) cause outbreaks. V. cholerae O1 has caused all recent outbreaks. The main reservoirs of V. cholerae are people and aquatic sources that are slightly salty and warm such as estuaries and some coastal areas. The cholera bacterium is usually found in water or food sources that have been contaminated by feces from a person infected with cholera. Cholera is most likely to be found and spread in places with inadequate water treatment, poor sanitation, and inadequate hygiene. Drinking this contaminated water is the most common cause of the transmission of cholera. It can take anywhere from a few hours to 5 days for symptoms to appear after infection. Cholera infection is often mild or without symptoms, but can sometimes be severe. Approximately 10% of infected persons will have severe disease characterized by profuse watery diarrhea, vomiting, and leg cramps. Rapid loss of body fluids leads to dehydration and shock. An important component of treatment is rehydration. Oral rehydration solution and intravenous fluids are vital in treating any cholera patient, due to the dehydration form diarrhea and vomiting. Antibiotics may include doxycycline, tetracycline, erythromycin, azithromycin, or ciprofloxacin. Zinc supplementation reduces the severity and duration of cholera and other diarrheal diseases in children in resource-limited areas.
Fig 1. Cholera cases reported to the World Health Organization (WHO) by year and continent. There is a clear resurgence in cholera cases in the Americas beginning in 2010.
References:
Ristuccia AM, Cunha BA, Current concepts in antimicrobial therapy of prostatitis. Urology 1982, 20, (3), 338-45
Wimberly BT, Structure of the 30S Ribosomal Subunit. Nature 2000, 407, (6802), 327-39
Sack DA, Islam S, Rabbani H, Islam A. Single-Dose Doxycycline for Cholera. Antimicrobial Agents and Chemotherapy 1978,14, (3), 462-4
The S4 protein is 23.359 kilodalton protein that is composed of 206 amino acids.
Fig 2. Representation of 30S ribosomal protein S4.
Location:
The 30S ribosomal subunit protein S4 is located on ribosomes in all cells.
Function in a normal cell:
This protein is one of two assembly initiator proteins for the 30S subunit. It binds directly to 16S rRNA where it nucleates (formation of a new structure via self-organization) assembly of the body of the 30S subunit. It plays an important role in translational accuracy, along with the S5 and S12 proteins. It can act as a translation repressor through negative regulation of translational initiation. The 30S subunit is an integral part of mRNA translation in prokaryotes. It binds three prokaryotic initiation factors: IF-1, IF-2, and IF-3. In addition, a portion of the 30S subunit (the16S rRNA) guides the initiating (5')-AUG codon of the mRNA into place by lining up a complementary sequence of RNA on the 16S subunit with the Shine-Dalgarno sequence on the mRNA. This ensures the ribosome starts translation at the correct location. Essentially, the S4 protein is essential for protein synthesis in bacteria.
Drug Information:
Schematic figure of drug:
Fig 3. Chemical structure of Doxycycline.
Formula: C22H24N2O8 Molecular weight: 444.4346 g/mol CAS Number: 564-25-0 Delivery method: Doxycycline is administered orally as a tablet or capsule. Side effects: Include nausea, upset stomach, mild diarrhea, skin rash or itching, or vaginal itching or discharge. Children under eight years of age should not take doxycycline as it can cause permanent discoloration of the teeth and enamel hypoplasia. Other names: Vibramycin Maker or company: Pfizer Is it patented? Yes Clinical Trials Info: Currently, there are two clinical trials involving doxycycline and cholera [8]. One was completed in 2008 by the International Centre for Diarrhoeal Disease Research, Bangladesh, and the other is ongoing and recruiting with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Origin: The first member of the tetracycline group was discovered in the late 1940s by Dr. Benjamin Duggar. It was derived from the soil-dwelling bacterium Streptomyces aureofaciens. Oxytetracycline was isolated soon after from S. rimosus by scientists at Pfizer Laboratories in 1950. This was further developed to Doxycycline. Doxycycline is a semi-synthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand Vibramycin. Vibramycin received FDA approval in 1967, becoming Pfizer's first once-a-day broad-spectrum antibiotic. Alternatives to this drug: Tetracycline, erythromycin, azithromycin, or ciprofloxacin. Miscellaneous: Other uses: can this drug be used to treat other diseases/conditions? Doxycycline can also be used as an antibiotic for a variety of other bacterial infections, like Rocky Mountain Spotted Fever, Typhus Fever, Plague, and Gonorrhea.
Disease/Drug of interest: Cholera/Doxycycline
Motivation and Background:
Cholera, an illness caused by the bacterium Vibrio cholerae, causes 21,000 to 143,000 deaths per year. This diarrheal disease is very painful and can be fatal for those who become infected. Antibiotic treatments, like doxycycline, are vital in accelerating treatment and making it less costly. This is important especially since cholera is prevalent in countries with poor access to healthcare and sanitation. Cholera is now endemic in fifty countries, including Haiti. Without treatment, death can occur within hours. Study on this disease and its treatment would be vital in saving hundreds of thousands of lives worldwide. This disease could be easily prevented if low-cost treatment and sanitary water were more accessible, but instead, thousands of people die from cholera every year.During the 1800s, cholera spread across the world from its origin in the Ganges delta in India. There were six subsequent pandemics that killed millions of people across all continents. The current pandemic started in South Asia in 1961, and reached Africa in 1971 and the Americas in 1991. It affects 1.3 to 4.0 million people per year. There are many strains of V. cholerae, but only two (O1 and O139) cause outbreaks. V. cholerae O1 has caused all recent outbreaks. The main reservoirs of V. cholerae are people and aquatic sources that are slightly salty and warm such as estuaries and some coastal areas. The cholera bacterium is usually found in water or food sources that have been contaminated by feces from a person infected with cholera. Cholera is most likely to be found and spread in places with inadequate water treatment, poor sanitation, and inadequate hygiene. Drinking this contaminated water is the most common cause of the transmission of cholera. It can take anywhere from a few hours to 5 days for symptoms to appear after infection. Cholera infection is often mild or without symptoms, but can sometimes be severe. Approximately 10% of infected persons will have severe disease characterized by profuse watery diarrhea, vomiting, and leg cramps. Rapid loss of body fluids leads to dehydration and shock. An important component of treatment is rehydration. Oral rehydration solution and intravenous fluids are vital in treating any cholera patient, due to the dehydration form diarrhea and vomiting. Antibiotics may include doxycycline, tetracycline, erythromycin, azithromycin, or ciprofloxacin. Zinc supplementation reduces the severity and duration of cholera and other diarrheal diseases in children in resource-limited areas.
References:
Ristuccia AM, Cunha BA, Current concepts in antimicrobial therapy of prostatitis. Urology 1982, 20, (3), 338-45
Wimberly BT, Structure of the 30S Ribosomal Subunit. Nature 2000, 407, (6802), 327-39
Sack DA, Islam S, Rabbani H, Islam A. Single-Dose Doxycycline for Cholera. Antimicrobial Agents and Chemotherapy 1978,14, (3), 462-4
External links:
https://clinicaltrials.govhttps://www.uspto.gov/web/patents/classification/uspcindex/indexd.htm
https://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/cholera
http://www.who.int/mediacentre/factsheets/fs107/en/
Target Information:
30S Ribosomal Subunit Protein S4Size:
The S4 protein is 23.359 kilodalton protein that is composed of 206 amino acids.Location:
The 30S ribosomal subunit protein S4 is located on ribosomes in all cells.Function in a normal cell:
This protein is one of two assembly initiator proteins for the 30S subunit. It binds directly to 16S rRNA where it nucleates (formation of a new structure via self-organization) assembly of the body of the 30S subunit. It plays an important role in translational accuracy, along with the S5 and S12 proteins. It can act as a translation repressor through negative regulation of translational initiation. The 30S subunit is an integral part of mRNA translation in prokaryotes. It binds three prokaryotic initiation factors: IF-1, IF-2, and IF-3. In addition, a portion of the 30S subunit (the16S rRNA) guides the initiating (5')-AUG codon of the mRNA into place by lining up a complementary sequence of RNA on the 16S subunit with the Shine-Dalgarno sequence on the mRNA. This ensures the ribosome starts translation at the correct location. Essentially, the S4 protein is essential for protein synthesis in bacteria.Drug Information:
Schematic figure of drug:
Formula:
C22H24N2O8
Molecular weight:
444.4346 g/mol
CAS Number:
564-25-0
Delivery method:
Doxycycline is administered orally as a tablet or capsule.
Side effects:
Include nausea, upset stomach, mild diarrhea, skin rash or itching, or vaginal itching or discharge.
Children under eight years of age should not take doxycycline as it can cause permanent discoloration of the teeth and enamel hypoplasia.
Other names: Vibramycin
Maker or company: Pfizer
Is it patented? Yes
Clinical Trials Info:
Currently, there are two clinical trials involving doxycycline and cholera [8]. One was completed in 2008 by the International Centre for Diarrhoeal Disease Research, Bangladesh, and the other is ongoing and recruiting with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
Origin:
The first member of the tetracycline group was discovered in the late 1940s by Dr. Benjamin Duggar. It was derived from the soil-dwelling bacterium Streptomyces aureofaciens. Oxytetracycline was isolated soon after from S. rimosus by scientists at Pfizer Laboratories in 1950. This was further developed to Doxycycline. Doxycycline is a semi-synthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand Vibramycin. Vibramycin received FDA approval in 1967, becoming Pfizer's first once-a-day broad-spectrum antibiotic.
Alternatives to this drug:
Tetracycline, erythromycin, azithromycin, or ciprofloxacin.
Miscellaneous:
Other uses: can this drug be used to treat other diseases/conditions?
Doxycycline can also be used as an antibiotic for a variety of other bacterial infections, like Rocky Mountain Spotted Fever, Typhus Fever, Plague, and Gonorrhea.